Chronic Myeloid Leukemia: Symptoms, Types, Causes and Treatment

Chronic Myeloid Leukemia (CML) is a complex blood cancer that has seen both diagnostic and therapeutic revolutions in recent decades. Understanding CML—its symptoms, the different types, what causes it, and the evolving landscape of treatment—is critical for patients, caregivers, and clinicians alike. This comprehensive guide synthesizes current research to offer a clear, in-depth overview of CML.

Symptoms of Chronic Myeloid Leukemia

CML often develops slowly, and many people may not notice symptoms in the early stages. However, as the disease progresses, symptoms can become more pronounced and sometimes quite unusual. Recognizing these signs is crucial for timely diagnosis and intervention.

Symptom	Description	Frequency/Significance	Source(s)
Fatigue	Persistent tiredness	Most common initial symptom	2 3 4 5
Splenomegaly	Enlarged spleen	Common clinical finding	2 3 4 5
Weight loss	Unintentional, rapid loss	Occurs in advanced phases	3 4 5
Night sweats	Excessive sweating during sleep	B symptom; variable frequency	4 5
Bone pain	Aching or tenderness	More frequent in advanced stages	3 4 5
Abdominal fullness	Sensation of abdominal distension	Linked to splenomegaly	3 4 5
Ocular symptoms	Vision changes, retinal issues	Rare but possible as initial sign	1
Thrombocytosis	High platelet count, clotting issues	Atypical, can cause complications	2
Infections	Recurring or persistent	Due to immune cell dysfunction	4 14

Table 1: Key Symptoms

Common and Early Symptoms

Most patients with CML are diagnosed during routine blood work, often before symptoms are noticeable. When symptoms do occur, fatigue is the most frequently reported, reflecting the body's struggle to cope with abnormal blood cell production. Other early signs include weight loss, night sweats, and low-grade fever—collectively known as "B symptoms"—which are more prominent in advanced disease stages 3 4 5.

Physical Findings

On examination, doctors may detect an enlarged spleen (splenomegaly) or liver (hepatomegaly). Patients might complain of abdominal fullness or early satiety, both consequences of organ enlargement pressing on the stomach or other structures 3 4 5.

Unusual or Atypical Presentations

While rare, CML can sometimes present with unusual symptoms. For example, some patients experience vision changes or eye pain due to leukemic infiltration of ocular structures (leukemic retinopathy, retinal detachment, or optic nerve involvement) 1. Others may have complications from exceedingly high platelet counts (thrombocytosis), such as clotting issues leading to syncope or heart attack 2. Because of these atypical presentations, clinicians must maintain a high degree of suspicion when evaluating unexplained symptoms alongside abnormal blood counts 2 5.

Infections and Bleeding

As the disease progresses, the body’s ability to produce normal blood cells decreases. This may result in anemia, increased susceptibility to infections, or easy bruising and bleeding due to low platelet counts 4 14.

Types of Chronic Myeloid Leukemia

CML is not a uniform disease—there are distinct forms and phases, each with unique features and clinical implications. Understanding these differences is key to proper diagnosis and effective treatment planning.

Type/Phase	Key Features	Clinical Impact	Source(s)
Chronic Phase	<15% blasts, gradual onset, mild symptoms	Most diagnosed here, best outlook	4 6 18
Accelerated Phase	15–30% blasts, worsening counts, organomegaly	Disease progression, high risk	4 6 18
Blast Phase (Crisis)	>30% blasts, severe symptoms, acute leukemia	Aggressive, urgent intervention	4 6 18
Atypical CML (aCML)	BCR-ABL1 negative, dysplasia, rare	Poorer prognosis, distinct entity	7 8 9 10

Table 2: Types and Phases of CML

Classical CML: The Three Phases

Chronic Phase

The vast majority of patients are diagnosed in the chronic phase, which may last several years. Here, white blood cell counts are high, but blasts (immature blood cells) are less than 15% of circulating white cells. Symptoms are usually mild, and treatment response is best at this stage 4 6 18.

Accelerated Phase

In this intermediate stage, the disease becomes more aggressive. Blast cells increase (15–30%), blood counts worsen, and organ enlargement (especially spleen and liver) becomes more pronounced. This phase may also be marked by new genetic mutations or additional chromosomal abnormalities 4 6 18.

Blast Phase (Blastic Crisis)

This resembles acute leukemia, with more than 30% blasts in the blood or bone marrow. Symptoms are severe, with profound fatigue, bone pain, fever, and infections. Rapid intervention is necessary, but prognosis is poor 4 6 18.

Atypical Chronic Myeloid Leukemia (aCML)

Atypical CML is a rare, distinct entity. Unlike classical CML, aCML is BCR-ABL1 negative and falls under the category of myelodysplastic/myeloproliferative neoplasms. It features marked leukocytosis, significant dysplasia (abnormal cell appearance), and a high risk of progression to acute myeloid leukemia. Mutations in genes such as SETBP1 and ETNK1 are commonly seen. Atypical CML has a poorer prognosis and limited treatment options, with hematopoietic stem cell transplantation currently being the only potential cure 7 8 9 10.

How Types Influence Diagnosis and Management

Correctly identifying the phase and type of CML directly influences treatment strategy and prognosis. For instance, tyrosine kinase inhibitors (TKIs) are highly effective in classical CML but not in aCML, which requires different management 18 8 9 10.

Causes of Chronic Myeloid Leukemia

CML is one of the best-understood cancers at the molecular level, with a clear genetic hallmark. Yet, its exact trigger in most individuals remains elusive.

Cause/Factor	Mechanism	Impact/Significance	Source(s)
Philadelphia Chromosome	t(9;22) translocation creates BCR-ABL1	Drives abnormal cell growth	3 4 11 12 15 18
Tyrosine Kinase Activity	Constitutive signaling via BCR-ABL1	Promotes proliferation	11 12 15
Additional Mutations	ASXL1, RUNX1, others in advanced phases	Disease progression, resistance	13
Unknown Environmental	Radiation, chemicals (rare, unclear)	Not clearly established	6 15

Table 3: Causes and Risk Factors

The Philadelphia Chromosome and BCR-ABL1 Fusion

At the heart of almost all CML cases is a specific genetic change: a reciprocal translocation between chromosomes 9 and 22, forming the "Philadelphia chromosome." This alteration creates the BCR-ABL1 fusion gene, which codes for a constitutively active tyrosine kinase enzyme. This abnormal enzyme signals hematopoietic (blood-forming) stem cells to divide uncontrollably, leading to the overproduction of white blood cells 3 4 11 12 15 18.

Tyrosine Kinase Activation

The BCR-ABL1 protein's unchecked signaling is why CML cells proliferate but do not mature normally. This understanding has been crucial for developing targeted therapies that specifically inhibit this abnormal kinase 11 12 15.

Additional Genetic Changes

As CML progresses, especially into the accelerated and blast phases, additional mutations often accumulate in genes such as ASXL1, RUNX1, and others. These secondary changes are linked to treatment resistance, more aggressive disease behavior, and transformation to acute leukemia 13.

Environmental and Other Factors

While the Philadelphia chromosome is the defining cause, the initial trigger for this genetic change is generally unknown. Rarely, exposure to high doses of ionizing radiation or certain chemicals has been linked to increased leukemia risk, but most cases arise without any identifiable environmental exposure 6 15.

Treatment of Chronic Myeloid Leukemia

The management of CML has evolved from limited options and poor outcomes to targeted therapies that allow many patients to live normal, healthy lives. Treatment approaches depend on disease phase, type, patient characteristics, and drug tolerance.

Treatment	Description/Approach	Indication/Outcome	Source(s)
Tyrosine Kinase Inhibitors (TKIs)	Target BCR-ABL1 (e.g., imatinib, dasatinib, nilotinib)	First-line for chronic phase, high remission rates	16 17 18 19
Allogeneic Stem Cell Transplant	Donor marrow replaces diseased cells	Curative, for advanced or TKI-resistant cases	6 16 17 19
Interferon Alpha	Immune-modulating agent	Used before TKIs; now less common	6 17
Hydroxyurea	Chemotherapy to reduce cell counts	Initial cytoreduction, less favored now	6 17
Plateletpheresis	Removes excess platelets	For severe thrombocytosis complications	2
Supportive Care	Transfusions, infection management	Symptom relief, palliative	4 6 14
Emerging/Targeted Agents	Ruxolitinib, trametinib, others	Trials for resistant/atypical cases	8 9 10 19

Table 4: Main Treatment Approaches

Tyrosine Kinase Inhibitors (TKIs)

The introduction of TKIs, such as imatinib, revolutionized CML treatment. These drugs block the abnormal BCR-ABL1 enzyme, halting disease progression and inducing long-term remissions in most chronic phase patients. Dasatinib, nilotinib, and bosutinib are newer TKIs used for patients resistant or intolerant to first-line therapy. Regular monitoring of response using molecular tests is essential 16 17 18 19.

Treatment-Free Remission

For patients who achieve a stable, deep molecular response, discontinuing TKIs for a treatment-free remission is now a realistic goal, though only a subset of patients are eligible 16.

Allogeneic Stem Cell Transplantation

Transplantation remains the only proven cure for CML. It is reserved for patients who do not respond to TKIs, have advanced disease, or have specific high-risk features. However, it carries significant risks and is best suited for younger, medically fit patients 6 16 17 19.

Other Agents: Interferon Alpha and Hydroxyurea

Before TKIs, interferon alpha and hydroxyurea were standard therapies. They are now mainly used for patients who cannot tolerate TKIs or in special circumstances 6 17.

Managing Complications and Special Situations

• Plateletpheresis: Used acutely if high platelet counts cause dangerous complications, such as clotting events 2.
• Supportive care: Includes blood transfusions, antibiotics, or medications to control symptoms like bone pain or infections 4 6 14.

Treatment of Atypical CML (aCML)

Atypical CML does not respond to TKIs due to the absence of BCR-ABL1. Hematopoietic stem cell transplantation is the only curative option. Emerging targeted therapies (e.g., ruxolitinib, trametinib) are being explored, but prognosis remains poor 8 9 10.

Conclusion

Chronic Myeloid Leukemia is a disease marked by remarkable scientific progress, yet it presents ongoing clinical challenges. Here are the key takeaways from this comprehensive review:

• Symptoms: CML often begins with subtle symptoms or is detected incidentally, but can manifest with fatigue, splenomegaly, weight loss, and, less commonly, unusual symptoms like visual changes or clotting complications.
• Types: Classical CML progresses through chronic, accelerated, and blast phases, while atypical CML (aCML) is a rare, aggressive form requiring different management.
• Causes: The Philadelphia chromosome and the resulting BCR-ABL1 fusion gene are central to CML, driving uncontrolled cell growth; additional mutations play a role in disease progression and drug resistance.
• Treatment: Tyrosine kinase inhibitors have revolutionized outcomes for most CML patients, but stem cell transplantation remains vital for TKI-resistant or advanced cases. Atypical CML is more challenging and is the focus of ongoing research into targeted therapies.

By staying informed about the evolving landscape of CML, patients and clinicians can work together towards the best possible outcomes—transforming what was once a fatal disease into a manageable, and increasingly curable, condition.